Atrial fibrillation (AF), a common arrhythmia, is associated with substantially elevated risks of stroke, cognitive decline, dementia, arterial emboli, heart failure, and cardiovascular death. Existing studies of AF generally investigate AF that has been clinically recognized, but studies in patients with implanted monitoring devices such as pacemakers or defibrillators indicate that a large proportion of AF episodes produce no symptoms at all and are undetected clinically. Furthermore, complications commonly attributed to AF, including embolic stroke, often occur in individuals with alterations of left atrial structure and function (atrial myopathy) but in the absence of clinically recognized AF. Therefore, clinical presentation with AF may represent a late stage in the pathophysiologic process linking atrial myopathy with serious complications including stroke and cognitive decline. New biomarkers are needed that reflect atrial myopathy and are highly predictive of AF and its complications. In the proposed research project, we will study newly developed heart rate (HR) fragmentation metrics computed from long-term electrocardiographic (ECG) recordings. Our preliminary data support the hypothesis that these new HR fragmentation metrics, developed by members of our investigative team, reflect breakdown of the neuroautonomic-electrophysiologic network controlling the sino-atrial node and its regulation of heart rate, and are highly predictive of both AF and cognitive impairment. In the setting of the Multi-Ethnic Study of Atherosclerosis (MESA), we propose to compute HR fragmentation indices from overnight ECG recordings and determine the association of HR fragmentation with cardiac structure assessed by MRI, with incident AF, and with brain structure and function assessed by MRI and cognitive testing. In exploratory analyses, we will use data from 14-day ambulatory ECG monitors to determine the short-term relationship of paroxysmal AF with HR fragmentation. Data from the Sleep Heart Health Study cohorts will be used to replicate findings from MESA for our primary aim. Our research will determine the extent to which HR fragmentation is a biomarker of altered left atrial structure and function, clinically recognized AF, and neurological complications of AF including impaired cognitive function and microvascular ischemia. With recent developments in mobile monitoring technology, noninvasive ambulatory ECG monitoring overnight or for longer periods is now practical. The measurement of HR fragmentation from these ECG recordings can be automated. Thus, if HR fragmentation is indeed a biomarker of atrial myopathy, AF, and its complications, information from noninvasive ECG monitoring may inform clinical care, including decisions about therapy to reduce the risk of stroke.